Dysfunction of Sensory Inhibition in Autism

描述(由申请人提供)：自闭症谱系障碍(ASD)是一组发育障碍，影响大约1%的儿童，患病率每年都在增加。ASD的分子基础可能是复杂和不同的，但鉴于抑制性神经递质GABA在认知控制、发育和可塑性中的核心作用，以及越来越多的证据将GABA能功能障碍与自闭症和自闭症表型联系起来，GABA系统是ASD研究的一个强大的潜在领域。最近，使用磁共振波谱(MRS)非侵入性地测量大脑中的GABA浓度已经成为可能，在一组非常新颖的实验中，我们已经证明了健康受试者之间局部GABA浓度的差异与可测量的行为相关。例如，感觉运动皮质中的GABA浓度与在躯体感觉辨别任务中的表现相关(见下文)；这可能与自闭症特别相关，因为对触觉刺激的非典型反应是自闭症的常见(和诊断)特征，并且可能显著损害行为功能。该建议源于Richard Edden博士(PI)和Stewart Mostofsky博士(Co-I)的合作，应用GABA的MRS与体感范例的极其新颖的配对来研究自闭症中是否存在可测量的GABA缺陷，以及这是否与自闭症在体感处理方面的差异有关。对GABA MRS及其与自闭症行为的关系的研究结果将为研究新的治疗方法，特别是使用增加GABA能活性的药物提供基础。在目标1中，我们将比较20名8岁至12岁ASD儿童和20名年龄、性别和智商匹配的典型发育中儿童(TDC)的GABA浓度测量结果。在目标2中，我们将进行触觉辨别的心理物理测量，以调查ASD儿童和TDC儿童之间是否存在差异，在目标3中，我们将测试ASD中常见的异常触觉加工是否源于GABA能缺陷。

DESCRIPTION (provided by applicant): Autism Spectrum Disorder (ASD) is a group of developmental disorders which affects approximately 1% of children, a prevalence rate that is increasing annually. The molecular basis of ASD is likely to be complex and heterogeneous, but given the central role of the inhibitory neurotransmitter GABA in cognitive control, development and plasticity and a growing body of evidence linking GABAergic dysfunction to autism and autistic phenotypes, the GABA system is a strong potential area for ASD research. Recently, it has become possible to measure GABA concentration non-invasively in the brain using magnetic resonance spectroscopy (MRS), and in an extremely novel set of experiments we have shown that differences in regional GABA concentration among healthy subjects have measurable behavioral correlates. For example, GABA concentration in sensorimotor cortex correlates with performance at a somatosensory discrimination task (see below); this may have particular relevance for autism, as atypical response to tactile stimuli is a common (and diagnostic) feature of autism and one that can substantially impair behavioral function This proposal arises from a collaboration between Dr Richard Edden (PI) and Dr Stewart Mostofsky (Co-I) to apply the extremely novel pairing of MRS of GABA with somatosensory paradigms to investigate whether there is a measurable GABA deficit in autism, and whether this correlates with autism associated differences in somatosensory processing. The findings from examination of GABA MRS and its association with autistic behavior will provide a foundation for investigating novel treatment therapies, specifically use of medications that increase GABAergic activity. In Aim 1, we will compare measurements of GABA concentration in a group of 20 children with ASD between the age of 8 and 12 years with 20 age-, gender-, and IQ-matched typically developing children (TDC) as the control group. In Aim 2, we will perform psychophysical measures of tactile discrimination to investigate whether there are differences between children with ASD and TDC, and in Aim 3 we will test whether the abnormal tactile processing commonly observed in ASD arises from a GABAergic deficit.